Enantioselective synthesis for the antipodes of slagenins B and C: establishment of absolute stereochemistry.

Article abstract of DOI:10.1021/ol016689+

[reaction: see text] The total synthesis for the (-)-antipode of slagenin B (12) and the (+)-antipode of slagenin C (13) was achieved with the condensation of glyoxal hydrate 10 and urea as the key step. The absolute stereochemistries of naturally isolated slagenins B and C were assigned to be (9R,11R,15R)-1b and (9R,11S,15S)-1c, respectively.

Full text of DOI:10.1021/ol016689+

ORGANIC
LETTERS
2001
Vol. 3, No. 25
4011-4013
Enantioselective Synthesis for the
Antipodes of Slagenins B and C:
Establishment of Absolute
Stereochemistry
Biao Jiang,* Jia-Feng Liu, and Sheng-Yin Zhao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China
jiangb@pub.sioc.ac.cn
Received September 4, 2001
ABSTRACT
The total synthesis for the (−)-antipode of slagenin B (12) and the (+)-antipode of slagenin C (13) was achieved with the condensation of
glyoxal hydrate 10 and urea as the key step. The absolute stereochemistries of naturally isolated slagenins B and C were assigned to be
(9R,11R,15R)-1b and (9R,11S,15S)-1c, respectively.
Several bromopyrrole alkaloids found in marine sponges have
been shown to exhibit pharmacologically useful activities
and include c-erbB-2 kinase and cyclin-dependent kinase 4
(cdk4) inhibitors, R-adrenoceptor blockers, serotonergic re-
ceptor antagonists, and antihistamine and actomyosin ATPase
activators, etc.1 Recently, Kobayashi et al. isolated a novel
class of alkaloids, slagenins A-C (1a-1c) (Figure 1), from
the Okinawan sponge Agelas nakamurai.2 These alkaloids
possess a unique tetrahydrofuro[2,3-d]imidazolidin-2-one
core in which the relative stereochemistry was elucidated
by NOESY spectroscopy. Although slagenins exhibit bio-
logical activities similar to those of other bromopyrrole
alkaloids, only preliminary tests have been carried out due
to the extremely small amount of samples available from
marine sources.2 While Horne and co-workers achieved the
first total synthesis of slagenins A-C,3 their absolute
stereochemistries have never been determined. We were
interested in developing an enantioselective synthetic method
for building the chiral tetrahydrofuro[2,3-d]imidazolidin-2-
one core and determining the absolute configurations of
naturally isolated slagenins B and C.
(1) Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1 and references therein.
(2) Tsuda, M.; Uemoto, H.; Kobayashi, J. Tetrahedron Lett. 1999, 40,
5709.
Figure 1. Structures of natural slagenins A-C.
(3) Sosa, A. C. B.; Yakushijin, K.; Horne, D. A. Org. Lett. 2000, 2,
3443.
10.1021/ol016689+ CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/21/2001

Slagenins possess a cis-fused tetrahydrofuro[2,3-d]imid-
azolidin-2-one moiety with three stereogenic centers. The
key of the synthetic scheme is the generation of these three
stereogenic centers in the tetrahydrofuro[2,3-d]imidazolidin-
2-one skeleton. Retrosynthetically, we considered that the
condensation reaction of glyoxal 3 and urea could be useful
for accessing intermediate 2 (Figure 2) on the basis of the
Scheme 1a
a Reagents and conditions: (a) H2, 0.1 mol % Ru(OAc)2(R-
BINAP), EtOH, 40 atm, 100 °C, 95%; (b) (1) TBSCl, imidazole,
DMF, 45 °C, and (2) NaN3, DMF, 90 °C, 85% for two steps; (c)
1,3-dithiane, n-BuLi, dry THF, -30 °C ∼ room temperature, 44%.
ester 6 was saponified to give acid 8, which was converted
into R-diazoketone 9 via the mixed anhydride by treatment
with ethereal diazomethane. Oxidation of diazoketone 9 using
distilled dimethyl-dioxirane (DMD)8 in acetone afforded a
mixture of glyoxal 3 and glyoxal hydrate 10 in quantitative
yield. The glyoxal was sensitive to air and could not be
purified by distillation or chromatography. Fortunately, the
crude product was pure enough to use in subsequent
reactions. With the key intermediate 3 and its hydrate 10 in
hand, we tried to cleave the tert-butyl dimethyl silyl ether.
Several conditions were tested for the cleavage, and most
gave complex results. Finally, we found that one-pot treat-
ment of the glyoxal mixture containing 3 and 10 with
aqueous HF and urea in methanol gave compound 2 in 50%
yield. The 1H NMR spectrum of 2 showed a 9:5 mixture of
two diastereoisomers 2a and 2b, which could not be
separated from each other by silica gel chromatography. We
inferred that the trans-fused bicycle was not present due to
the obvious strain of a trans [3.3.0]bicycle and that isomer
2a predominated over isomer 2b as a result of intramolecular
steric hindrance. However, separation of the diastereomers
required further elaboration of the core. Therefore, the azido
group in intermediate 2 was reduced to an amino group by
hydrogenation over 10% Pd/C in methanol, and the amine
was then acylated with 4-bromo-2-(trichloroacetyl)pyrrole
to give a 9:5 ratio of compounds 12 and 13 in 80% yield for
two steps (Scheme 2).
Compounds 12 and 13 were separated by silica gel
chromatography, allowing us to firmly establish the stereo-
chemistries of both compounds and therefore confirm the
stereochemistries inferred for diastereomers 2a and 2b. The
NMR, IR, and mass spectral data for compound 12 were in
satisfactory agreement with those reported for synthetic and
naturally isolated slagenin B, while the data for compound
13 agreed well with those for synthetic and naturally isolated
slagenin C.2-3 The NOESY spectrum of 12 showed correla-
tions for H-9 to both H-12 and H-14, H-15 to H3-16, H-10â
to H-7, and H-10â to H-15, indicating that the bicycle of 12
was cis-fused and that H-9, H-15, and the methoxy group at
Figure 2. Retrosynthesis of slagenins B and C.
relevant synthesis of dihydroxyimidazolidin and glycoluril
from glyoxal and urea (eq 1).4 In this synthetic plan, another
key issue that must be addressed is the generation of the
chiral intermediate 3 so that the other two stereogenic centers
can be induced.
Hydrogenation of commercially available ethyl 4-chloro-
acetoacetate (4) over Ru(OAc)2(R-BINAP) afforded ethyl-
(S)-4-chloro-3-hydroxybutanonate (5) in 95% yield (97%
enantiomeric excess (ee)).5 The 3-hydroxy group was
protected as a tert-butyl dimethyl silyl ether, and then the
4-chloro group was displaced with azide, giving compound
6. Next, the carbon chain was elongated with 1,3-dithiane
to obtain thioketal 7. Unfortunately, all attempts to cleave
the thioketal were unsuccessful6 (Scheme 1).
We next considered the synthesis of the glyoxal 3 from
an R-diazoketone. Prato et al. reported a mild and efficient
process for preparing achiral labile R-oxo-aldehydes by the
oxidation of R-diazoketones with dimethyl-dioxirane.7 Thus,
(4) (a) Grillon, E.; Gallo, R.; Pierrot, M.; Boileau, J.; Wimmer, E.
Tetrahedron Lett. 1988, 29, 1015. (b) Gautam, S.; Katcham, R.; Nematollahi,
J. Synthetic Commun. 1979, 9, 863. (c)Vail, S. L.; Barker, R. H.; Mennitt,
P. G. J. Org. Chem. 1965, 30, 2179.
(5) (a) Ager, D. J.; Laneman, S. A. Tetrahedron: Asymmetry 1997, 8,
3327. (b) Davies, S. G.; Ichihara, O. Tetrahedron: Asymmetry 1996, 7,
1919. (c) Yuasa, Y.; Tsuruta, H. Liebigs Ann. Chem. 1997, 1877.
(6) (a) Juaristi, E.; Tapia, J.; Mendez, R. Tetrahedron 1986, 42, 1253.
(b) Corey, E. J.; Bock, M. G. Tetrahedron Lett. 1975, 2643. (c) Cossy, J.
Synthesis 1987, 1113. (d) Prato, M.; Quinity, U.; Scorrano, G.; Sturaro, A.
Synthesis 1982, 679.
(8) (a) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377. (b) Bull, J, R.; Dekoning, P. D. Eur. J. Org. Chem. 2001, 1189. (c)
Rainier, J. D.; Allcrein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66, 1380.
(7) Ihmels, H.; Maggini, M.; Prato, M.; Scorrano, G. Tetrahedron Lett.
1991, 32, 6215.
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Org. Lett., Vol. 3, No. 25, 2001

Scheme 2a
Figure 3. Structures of 12 and 13.
13 {[R]20D ) +35.0° (c 0.2, MeOH)} with that of naturally
isolated slagenin C {[R]25 ) -35° (c 0.2, MeOH)}
D
suggested that the absolute structure of naturally isolated
slagenin C should be (9R,11S,15S)-1c (Figure 1).
In summary, a short total synthesis for the (-)-antipode
of slagenin B and the (+)-antipode of slagenin C has been
accomplished. An enantioselective synthetic approach for
preparing the cis-fused tetrahydrofuro[2,3-d]imidazolidin-2-
one skeleton from glyoxal hydrate and urea has been devel-
oped. Furthermore, the absolute structures of naturally iso-
lated slagenins B and C were established to be (9R,11R,15R)-
1b and (9R,11S,15S)-1c, respectively, by comparison with
the enantioselectively synthesized antipodes of slagenins B
and C.
a Reagents and conditions: (a) (1) 2 equiv LiOH, acetone-water,
room temperature, and (2) H+, 95%; (b) (1) isobutyl chlorocar-
bonate, NEt3, dry THF, -20 °C ∼ -10 °C, and (2) 2 equiv ethereal
diazomethane, 90%; (c) DMD-acetone, 100%; (d) 40% aqueous
HF, 2.5 equiv urea, methanol, room temperature, 50%; (e) H2, Pd/
C, methanol; (f) 4-bromo-2-(trichloroacetyl)pyrrole, DMF, room
temperature, 80% for two steps.
Acknowledgment. We thank Prof. David A. Horne
(Oregon State University) for providing NMR data for
synthetic Slagenins. We are also grateful for financial support
from the Shanghai Municipal Committee of Science and
Technology.
C-11 were R-, â-, and â-oriented, respectively. For compound
13, the NOESY correlations for H-9 to H-15 and for H-15
to H3-16 implied that H-9, H-15, and the methoxy group at
C-11 were all â-oriented. Therefore, the absolute structures
of 12 and 13 were respectively assigned to be (9S,11S,15S)-
12 and (9S,11R,15R)-13 (Figure 3). Comparison of the
Supporting Information Available: Spectroscopic data
and experimental procedures for compounds 2, 3 and 10,
1
5-9, and 12-13; H NMR spectra for compounds 2 and 3
1
and 10; H and 13C NMR spectra for compounds 6, 8-9,
negative specific rotation of 12 {[R]20 ) -45.4° (c 0.5,
D
and 12-13; NOESY spectra for compounds 12-13. This
material is available free of charge via the Internet at
http://pubs.acs.org.
MeOH)} with the positive specific rotation of naturally
isolated slagenin B {[R]26D ) +33° (c 0.2, MeOH)} revealed
that the naturally isolated slagenin B has a (9R,11R,15R)-
configuration, while comparison of the specific rotation of
OL016689+
Org. Lett., Vol. 3, No. 25, 2001
4013